The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of prolonged depression and apathy similar to the negative symptoms seen in schizophrenics. Similarly, in rats, the chronic administration of high doses of cocaine can produce a decrease in locomotor activity and a lack of the usual sensitization state seen with lower dose stimulant drug challenge. In the present study, we evaluated the effects of cocaine administration on the uptake of dopamine in three brain areas of the rat. Cocaine (10 mg/kg) was administered intraperitoneally twice a day for 7 days. The animals were sacrificed two weeks after the last injection, and the uptake of 3H-dopamine into synaptosomes from the prefrontal cortex, striatum and nucleus accumbens was examined. Control animals consisted of rats injected on the same schedule with saline. Animals receiving cocaine exhibited a significant decrease in locomotor activity as compared to the saline-treated rats. In addition, the locomotor responses of these animals to a challenge dose of cocaine (2.5 and 5.0 mg/kg) or amphetamine (1 mg/kg) were the same. The uptake of 3H-dopamine into synaptosomes of the prefrontal cortex of cocaine-treated rats was significantly decreased (30%) as compared to the saline-treated rats. There were no significant differences between these groups of rats in dopamine uptake in the striatum or nucleus accumbens. Kinetic analysis of the data indicated that the decrease in dopamine uptake in the prefrontal cortex of the cocaine-treated rats was due to a decrease in the Vmax of the uptake pump for dopamine. GBR12909, a selective inhibitor of dopamine uptake, and cocaine inhibited 3H-dopamine uptake into the prefrontal cortex, striatum and nucleus accumbens in a similar manner. Treatment of rats with methamphetamine, using the same paradigm, did not produce any changes in dopamine uptake in the three brain areas, indicating that cocaine was selective in producing the decrease in dopamine uptake in the prefrontal cortex.